CN108079009A - A kind of pharmaceutical composition for being used to treat senile dementia disease - Google Patents

A kind of pharmaceutical composition for being used to treat senile dementia disease Download PDF

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Publication number
CN108079009A
CN108079009A CN201611038340.9A CN201611038340A CN108079009A CN 108079009 A CN108079009 A CN 108079009A CN 201611038340 A CN201611038340 A CN 201611038340A CN 108079009 A CN108079009 A CN 108079009A
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pharmaceutical composition
weight
parts
radix polygalae
polysaccharide
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裴钢
黄成钢
赵简
李志雄
侯羽君
高羽
李晓行
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/075Ethers or acetals
    • A61K31/085Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024Esters of saccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06Fungi, e.g. yeasts
    • A61K36/07Basidiomycota, e.g. Cryptococcus
    • A61K36/076Poria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/69Polygalaceae (Milkwort family)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • A61K36/888Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The present invention relates to a kind of for treating the pharmaceutical composition of senile dementia disease, specifically, the pharmaceutical composition includes following active ingredient and pharmaceutically acceptable carrier;Wherein, the active ingredient is selected from the group:Pachymic acid, alpha-ararin, β-asarone, tenuifolin, polygalic acid B, Radix Polygalae

Description

A kind of pharmaceutical composition for being used to treat senile dementia disease
Technical field
The present invention relates to a kind of for treating pharmaceutical composition of senile dementia disease and its preparation method and application.More Body, the present invention relates to active ingredient in fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia compound medicament composition and its Prepare the purposes in treatment senile dementia disease medicament.
Background technology
Senile dementia is the disease of a kind of chronic progressive occurred in the senescence phase or stage advance mental deterioration, mainly Vascular caused by being divided into senile dementia (Alzheimer disease, AD) and cerebrovascular disorder including primary brain retrogression Dull-witted (VD), mixed dementia and other dementias, but it is the most common with AD, VD two types, account for more than the 90% of all dementias. AD is a kind of central nervous system degenerative disease, characterized by higher cognitive dysfunction, with senile plaque expelling, neurofibrillary tangles It is the comprehensive disease of main pathological change with neuron loss.The harmfulness of senile dementia is very big, not only hinders patient's emotion personality Hinder, cognition dysfunction, memory dysfunction, linguistic function obstacle, visual space dysfunction, personal care's ability barrier Hinder, social-life ability obstacle;And the huge burden on society thus brought is had become as important public health problem, to society Economic development causes certain resistance.In developed country, the death rate of senile dementia is only second to heart disease, tumour, apoplexy and occupies 4th.As world population is increasingly aging, the disease have become that current gerontology faces it is most severe the problem of one of.
The chemicals for the treatment of senile dementia all simply delays and mitigates patient symptom at present, is only symptomatic treatment, also Its course of disease cannot be had an impact.Obvious existing treatment means are also far from meeting phase of the patient to curative effect and treatment final result It treats.Though record of the traditional Chinese medical science without senile dementia name of disease from the point of view of symptom, belongs to " dementia " of the traditional Chinese medical science, " forgetful ", " insane The scope of the diseases such as disease ".But the research of effective component of chinese medicine treatment senile dementia is started late, and research is relatively fewer, serious to make About Chinese medicine deeply developing and evaluates.
In conclusion in order to treat senile dementia disease, there is an urgent need in the art to develop new treatment senile dementia disease Drug, especially active ingredient derive from Chinese medicine drug.
The content of the invention
The first aspect of the present invention provides a kind of pharmaceutical composition for being used to treat senile dementia disease, the medicine Compositions include following active ingredient and pharmaceutically acceptable excipient, carrier, adjuvant or its combination;
Wherein, the active ingredient is selected from the group:It is pachymic acid, alpha-ararin, β-asarone, tenuifolin, remote Will saponin(e B, Radix PolygalaeKetone III, pachymaran, grass-leaved sweetflag polysaccharide, Radix Polygalae polysaccharide or its combination.
In another preference, the pharmaceutical composition contains 3~9 kinds of the active ingredient.
In another preference, the pharmaceutical composition contains 6~9 kinds of the active ingredient.
In another preference, the pharmaceutical composition contains 8~9 kinds of the active ingredient.
In another preference, in the pharmaceutical composition described in the pharmaceutical composition:
The content of pachymic acid be more than 0.05wt% and/or
The content of alpha-ararin be more than 0.01wt% and/or
The content of β-asarone be more than 0.1wt% and/or
The content of tenuifolin be more than 0.3wt% and/or
The content of polygalic acid B be more than 0.2wt% and/or
Radix PolygalaeThe content of ketone III be more than 0.05wt% and/or
The content of pachymaran be more than 1.0wt% and/or
The content of grass-leaved sweetflag polysaccharide be more than 1.0wt% and/or
The content of Radix Polygalae polysaccharide is more than 1.0wt%,
And pharmaceutically acceptable excipient, carrier, adjuvant or its combination of surplus;More than content presses the medicine The gross weight meter of compositions.
In another preference, the pharmaceutical composition further includes auxiliary element selected from the group below:Poria cocos eo-acid A, Fu Siberian cocklebur eo-acid B, Roots of Polygala tenuifolia glycosides A, 3,6 '-two mustard acyl sucrose or its combination.
In the second aspect of the present invention, a kind of pharmaceutical composition for being used to treat senile dementia disease is provided, it is described The active ingredient of pharmaceutical composition includes the active ingredient in fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia;
And the active ingredient in the fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia includes:Pachymic acid, alpha-ararin, β-asarone, tenuifolin, polygalic acid B, Radix PolygalaeKetone III, pachymaran, grass-leaved sweetflag polysaccharide and Radix Polygalae polysaccharide.
It is as follows containing effective active composition in the pharmaceutical composition in another preference:
The pachymic acid of 2-10 parts by weight;
The alpha-ararin of 1-10 parts by weight;
β-asarone of 1-20 parts by weight;
The tenuifolin of 5-50 parts by weight;
The polygalic acid B of 3-30 parts by weight;
The Radix Polygalae of 1-10 parts by weightKetone III;
The pachymaran of 20-200 parts by weight;
The grass-leaved sweetflag polysaccharide of 20-200 parts by weight;
The Radix Polygalae polysaccharide of 20-200 parts by weight;
And the total weight of the effective active composition accounts for the 20-99% of pharmaceutical composition total weight and the pharmacy of surplus Upper acceptable excipient, carrier, adjuvant or its combination.
It is as follows containing effective active composition in the pharmaceutical composition in another preference:
The pachymic acid of 3-4 parts by weight;
The alpha-ararin of 3-4 parts by weight;
β-asarone of 4-6 parts by weight;
The tenuifolin of 8-10 parts by weight;
The polygalic acid B of 4-8 parts by weight;
The Radix Polygalae of 3-6 parts by weightKetone III;
The pachymaran of 30-100 parts by weight;
The grass-leaved sweetflag polysaccharide of 20-100 parts by weight;
The Radix Polygalae polysaccharide of 30-100 parts by weight;
And the total weight of the effective active composition accounts for the 50-99% of pharmaceutical composition total weight.
The third aspect of the present invention provides a kind of use of the pharmaceutical composition as described in first aspect and second aspect On the way, the pharmaceutical composition is used to prepare the drug for the treatment of senile dementia.
In another preference, the senile dementia includes:Alzheimer disease, Parkinson's disease, Huntingdon formula Vascular dementia and mixed dementia caused by disease, creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, cerebrovascular disorder.
It is to be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to form new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Description of the drawings
The invisible platform escape latency of Fig. 1 mouse.
Fig. 2 mouse target quadrant search times:*, negative transgenosis group vs AD- control groups, t examine P=0.005;#, AD- Control group vs AD- reagent groups, P=0.038.
Fig. 3 mouse swimming rate (cm/s, cm/s):ANOVA analyses are without difference, P=0.673 between each group.
Specific embodiment
The present inventor is by in-depth study extensively, it has unexpectedly been found that in fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia The composition that is formed by a certain percentage of active ingredient, can obviously improve the learning memory disorder of AD mouse.Poria cocos, grass-leaved sweetflag and Radix Polygalae crude extract also has certain anti-AD activity, but active ingredient composition drug effect statistics after purification is better than crude extract. The present invention is completed on this basis.
The Chinese medicine being related to of the present invention has the following properties that and effect:
Fushen:Nature and flavor are sweet, light flat.The thoughts of returning home, the spleen channel.There is excreting dampness, invigorating the spleen, calming heart etc..For phlegm and retained fluid, oedema, small Just unfavorable, diarrhea, palpitaition, dizziness.
Poria cocos:It is sweet in flavor, light, it is mild-natured.The thoughts of returning home, lung, spleen, kidney channel.With functions such as clearing damp and promoting diuresis, invigorating the spleen, calming hearts.For water Swollen oliguria, phlegm retention anti-dazzle nervous, spleen eating less, loose stool diarrhea, confused and worried, insomnia of palpitating with fear.
Grass-leaved sweetflag:Nature and flavor acrid, bitter, warm.The thoughts of returning home, stomach.With dampness elimination appetizing, slit phlegm of having one's ideas straightened out, the functions such as inducing resuscitation intelligence development.With In gastral cavity ruffian is not hungry, apnea, coma epilepsy, forgetfulness and deafness.
Radix Polygalae:It is bitter in taste, pungent, tepor.The thoughts of returning home, kidney, lung channel.With functions such as tranquilize the mind and promote the intelligence, eliminating the phlegm, detumescences.For the heart Kidney does not hand over caused insomnia and dreamful sleep, and forgetful palpitation with fear is wandering, and expectoration is not well, sore swollen toxin, mastosis.
As used herein, term " effective active composition " refer in fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia it is effective into Point, including:Pachymic acid, alpha-ararin, β-asarone, tenuifolin, polygalic acid B, Radix PolygalaeKetone III, pachymaran, Grass-leaved sweetflag polysaccharide and Radix Polygalae polysaccharide.Wherein, pachymic acid and the extract component that pachymaran is fushen or Poria cocos, alpha-ararin, β- Asarone and the extract component that grass-leaved sweetflag polysaccharide is grass-leaved sweetflag, tenuifolin, polygalic acid B, Radix PolygalaeKetone III and Radix Polygalae Polysaccharide is the extract component of Radix Polygalae.In the present invention, in addition to using above-mentioned effective active composition, can also use described has Imitate the salt of active ingredient, such as pharmaceutically acceptable salt hydrochlorate, sulfate, acetate, mesylate etc..
As used herein, term " auxiliary element " refer in complementary fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia into Point, including Poria cocos eo-acid A, Poria cocos eo-acid B, Roots of Polygala tenuifolia glycosides A, 3,6 '-two mustard acyl sucrose.
As used herein, term " comprising " include " containing ", " substantially by ... form " and " by ... form ".
As used herein, term " substantially by ... form " refers in pharmaceutical composition, except contain effective active into Point or auxiliary element outside, also containing submember and/or impurity a small amount of and that do not influence active ingredient.For example, can be with Containing sweetener to improve taste, antioxidant to prevent block and other additives commonly used in the art.Usual Poria cocos Acid, alpha-ararin, β-asarone, tenuifolin, polygalic acid B, Radix PolygalaeKetone III, pachymaran, grass-leaved sweetflag polysaccharide and Radix Polygalae polysaccharide accounts at least the 30% of whole pharmaceutical composition weight, preferably at least 60%, more preferably at least 90%.
As used herein, term " pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various taxes Shape agent and diluent.The term refers to some such medicament carriers:Themselves it is not necessary active ingredient, and does not have after applying There is undue toxicity.Suitable carrier is well known to those of ordinary skill in the art.In Remington's It can be found on pharmaceutically acceptable figuration in Pharmaceutical Sciences (Mack Pub.Co., N.J.1991) Agent discusses fully.Pharmaceutically acceptable carrier can contain liquid in the composition, such as water, brine, glycerine and ethyl alcohol.Separately Outside, there is likely to be complementary substances, such as wetting agent or emulsifier, pH buffer substance in these carriers.Come from fushen Or Poria cocos, the functionality in addition to effective active composition of grass-leaved sweetflag and Radix Polygalae and other functionalities (such as its His complementary medicinal material), it is also included in the definition of pharmaceutically acceptable carrier.
As used herein, term " composition of the invention " includes pharmaceutical composition and dietary supplement, as long as they contain Have or substantially by pachymic acid, alpha-ararin, β-asarone, tenuifolin, polygalic acid B, Radix PolygalaeKetone III, Poria cocos Polysaccharide, grass-leaved sweetflag polysaccharide and Radix Polygalae polysaccharide isoreactivity ingredient are formed.In general, the weight of above-mentioned active ingredient accounts for composition total weight 20-99%, preferably 50-99%, more preferably 60-99%.
In addition, other substances of the present composition containing treatment senile dementia disease.
Pharmaceutical composition of the present invention is closely related to the therapeutic effect of senile dementia disease and the content of effective active composition. Research shows to obtain stable therapeutic effect, and effective active composition content in pharmaceutical composition should be made to reach certain model It encloses, for example, pachymic acid, content is more than 0.05wt%;Alpha-ararin, content are more than 0.01wt%;β-asarone, content are more than 0.1wt%;Tenuifolin, content are more than 0.3wt%;Polygalic acid B, content are more than 0.2wt%;Radix PolygalaeKetone III, contains Amount is more than 0.05wt%;Pachymaran, content are more than 1.0wt%;Grass-leaved sweetflag polysaccharide, content are more than 1.0wt%;Radix Polygalae polysaccharide, Content is more than 1.0wt%.
In addition to limiting the composition of the present invention by necessary active ingredient, matching somebody with somebody for necessary component (medicinal material) also can use Than come limit the present invention pharmaceutical composition.
In the compositions of the present invention, by weight, the appropriate proportioning of several effective active compositions is:
The substance of surplus is pharmaceutically acceptable carrier, such as starch, maltodextrin etc..
The pharmaceutical composition or dietary supplement of the present invention, can be made any conventional preparation shape by conventional method Formula, preferably tablet, capsule preparations, granule, pill, oral liquid, injection etc..
Pharmaceutical composition of the present invention has carried out multiple animal experiments, and the use link that treatment disease is put into the medicine provides Science and objective foundation.Its result of the test shows that the pharmaceutical composition has the note to reproducibility dysmnesia mouse caused by ethyl alcohol Recall improvement result, the learning memory disorder of AD mouse can be obviously improved.
The advantage of the invention is that:
(1) it is clear and definite and with strong points that simplicity, active ingredient are prepared;
(2) quantitative control can be carried out to active ingredient, so as to ensure quality;
(4) it is evident in efficacy, it is safe.
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to conventional strip Part or according to the condition proposed by manufacturer.Unless otherwise stated, otherwise percentage is weight percentage, and number is weight Number.
Prepare embodiment 1
Fushen, grass-leaved sweetflag, each 200 grams of Radix Polygalae are weighed, adds in the water of 6.0L, after impregnating 30 minutes, water boiling and extraction 2 times, When each decocting time is 1.5 small, No. 2 times extracting solution merges, filtering, is concentrated under reduced pressure into relative density as 1.29 (60 DEG C), thick paste Dries pulverizing obtains extract.Through high effective liquid chromatography for measuring, Poria cocos acid content is 0.08% in extract, and alpha-ararin contains It is 0.18% to measure as 0.03%, β-asarone content, and tenuifolin content is 0.48%, and polygalic acid B content is 0.73%, Radix PolygalaeKetone III contents are 0.06%.Total starches content is measured as 7.95% through ultraviolet spectrophotometry.
Prepare embodiment 2 --- the preparation of Poria cocos, grass-leaved sweetflag and Radix Polygalae mixed extract
Grass-leaved sweetflag 500g and Radix Polygalae 250g are weighed, adds 10 times of 60% ethyl alcohol of amount, refluxing extraction 2 times, each 2h, extracting solution closes And filter, ethyl alcohol is recovered under reduced pressure, continues to be concentrated under reduced pressure into relative density as 1.28 (60 DEG C), thick paste dries pulverizing obtains stone Chang Pu and Radix Polygalae mixed extract.Take Poria cocos medicinal material 250g, add 8 times amount water decoct it is secondary, every time 1.5 it is small when, collecting decoction, filter It crosses, filtrate decompression concentration, thick paste dries pulverizing obtains tuckahoe extracts.Above-mentioned grass-leaved sweetflag and Radix Polygalae mixed extract and Poria cocos Extract is with 3:1 ratio merges to get grass-leaved sweetflag, Radix Polygalae and Poria cocos mixed extract.
Prepare embodiment 3 --- the preparation of pachymic acid
Poria cocos 500g, add 8 times amount 90% ethyl alcohol, refluxing extraction 2 times, every time 2 it is small when, filter, subtract after extracting solution is merged Concentration and recovery ethyl alcohol is pressed, continues to be concentrated under reduced pressure into relative density as 1.28 (60 DEG C);More than thick paste adds 3L moisture to dissipate, and uses petroleum ether Extraction 3 times removes petroleum ether extraction liquid, and remaining water mutually extracts 3 times through ethyl acetate, and combined ethyl acetate extract liquor is recycled to It is dry, obtain the Poria cocos acid crude of Dark grey;Silica gel column chromatography (1 is carried out to more than crude product:20, g/g), with petroleum ether:Acetone=8:1 It is eluted, and carries out thin-layer chromatography detection, flow point containing pachymic acid is merged according to thin-layer chromatography situation, then through acetone recrystallization, Obtain pachymic acid.
Prepare embodiment 4 --- the preparation of tenuifolin
Polygala tenuifolia 250g adds in 6 times of amount 75% ethanol solution heating and refluxing extractions 3 times, each 1.5h, merges extracting solution Filtering, decompression filtrate recycling ethanol continue to be concentrated under reduced pressure into 500ml, add in 10%NaOH solution 1200ml, it is small to be heated to reflux 2 When, concentrated hydrochloric acid is added in after cooling and adjusts pH, pH value is made to be sufficiently stirred for 4.0, with equivalent extracting n-butyl alcohol 2 times, combining extraction liquid Solvent is recovered under reduced pressure to doing, solvent is recovered under reduced pressure to doing in combining extraction liquid, and residue is through silica gel column chromatography, with ethyl acetate:Second Alcohol:Water (15:2:1~10:2:1) elute, and carry out thin-layer chromatography detection, soap containing Roots of Polygala tenuifolia is merged according to thin-layer chromatography situation Glycosides flow point with 95% ethyl alcohol recrystallization, obtains tenuifolin.
Prepare embodiment 5 --- the preparation of polygalic acid B
Polygala tenuifolia 500g adds in 8 times of amount 85% ethanol solution heating and refluxing extractions 3 times, each 2h, merges extracting solution mistake Filter, decompression filtrate recycling ethanol continues to be concentrated under reduced pressure into 800ml, successively with the petroleum ether of 500ml, extracting n-butyl alcohol 3 times, closes And solvent is recovered under reduced pressure to doing in butanol extraction liquid, obtains n-butyl alcohol extract.Silica gel column chromatography (1 is carried out to gained dry powder:30, G/g), with chloroform:Methanol:Water=2.5:1:1~1:1:1 is eluted, and carries out thin-layer chromatography detection, according to thin-layer chromatography feelings Condition merges, and is concentrated to dryness, then it is recrystallized with methanol, obtains polygalic acid B..
Prepare embodiment 6 --- Radix PolygalaeThe preparation of ketone III
Polygala tenuifolia 500g adds in 6 times of amount 75% ethanol solution heating and refluxing extractions 2 times, each 2h, merges extracting solution mistake Filter, decompression filtrate recycling ethanol continues to be concentrated under reduced pressure into 700ml, using dichloromethane extraction concentrate 3 times, is concentrated under reduced pressure two Chloromethane alkane extract obtains medicinal extract;Above-mentioned medicinal extract is separated using silica gel column chromatography:1 is pressed with dichloromethane and methanol:0~0:1 The mixed solution that volume ratio is formed carries out gradient elution, and the fraction containing Radix Polygalae mouth mountain ketone III is collected in thin-layer chromatography detection;It is right More than Radix PolygalaeThe fraction of ketone III carries out inverted silica gel column chromatography separation, and 2 are pressed with methanol and water:8~9:1 volume ratio shape Into mixed solution carry out gradient elution, thin-layer chromatography detection collects the fraction containing Radix Polygalae mouth mountain ketone III, then with methanol pair It is recrystallized, and obtains Radix PolygalaeKetone III.
Prepare embodiment 7 --- the preparation of pachymaran
Poria cocos medicinal material 500g adds 8 times of amount water to decoct 2 times, every time 2 it is small when, collecting decoction, filtration, filtrate decompression is concentrated into Relative density is 1.25 (60 DEG C), is let cool, and it is 65% that ethyl alcohol is added, which to make containing amount of alcohol, is stood overnight, and precipitation and separation is simultaneously dried in vacuo, It crushes, sieving obtains pachymaran extract.
Prepare embodiment 8 --- the preparation of grass-leaved sweetflag polysaccharide
Grass-leaved sweetflag 500g adds 8 times of amount water to decoct 2 times, every time 1.5 it is small when, collecting decoction, filtration, filtrate decompression is concentrated into Relative density is 1.24 (60 DEG C), is let cool, and it is 70% that ethyl alcohol is added, which to make containing amount of alcohol, is stood overnight, and precipitation and separation is simultaneously dried in vacuo, It crushes, sieving obtains grass-leaved sweetflag polyoses extract.
Prepare embodiment 9 --- the preparation of Radix Polygalae polysaccharide
Take Polygala tenuifolia 500g, 8 times of amount water added to decoct 2 times, every time 1.5 it is small when, collecting decoction, filtration, filtrate decompression is dense Relative density is reduced to as 1.25 (60 DEG C), is let cool, it is 70% that ethyl alcohol is added, which to make containing amount of alcohol, is stood overnight, precipitation and separation and vacuum It dry, pulverize, sieve, obtain Radix Polygalae polyoses extract.
Prepare embodiment 10 --- the preparation of pharmaceutical composition
For treating the pharmaceutical composition of senile dementia disease, it is made of the raw material of following parts by weight:Pachymic acid 3 Part, 2 parts of alpha-ararin (being purchased from Jinan Hai Liheng Pharmaceutical Technology Co., Ltd), 4 parts of β-asarone (are purchased from the permanent medicine of Jinan sea power Science and Technology Ltd.), 10 parts of tenuifolin, 8 parts of polygalic acid B, 3 parts of Radix Polygalae mountain ketone III, 35 parts of pachymaran, stone 20 parts of calamus polysaccharide, 30 parts of Radix Polygalae polysaccharide.
Prepare embodiment 11 --- the preparation of pharmaceutical composition
For treating the pharmaceutical composition of senile dementia disease, it is made of the raw material of following parts by weight:Pachymic acid 4 Part, 4 parts of alpha-ararin (being purchased from Jinan Hai Liheng Pharmaceutical Technology Co., Ltd), 10 parts of tenuifolin, polygalic acid B 6 Part, 30 parts of pachymaran, 20 parts of grass-leaved sweetflag polysaccharide, 40 parts of Radix Polygalae polysaccharide.
Prepare embodiment 12 --- the preparation of pharmaceutical composition
For treating the pharmaceutical composition of senile dementia disease, it is made of the raw material of following parts by weight:Alpha-ararin 3 Part (being purchased from Jinan Hai Liheng Pharmaceutical Technology Co., Ltd), 10 parts of tenuifolin, 5 parts of polygalic acid B.
Prepare embodiment 13 --- the preparation of pharmaceutical composition
For treating the pharmaceutical composition of senile dementia disease, it is made of the raw material of following parts by weight:Alpha-ararin 3 Part (being purchased from Jinan Hai Liheng Pharmaceutical Technology Co., Ltd), 8 parts of tenuifolin, 4 parts of polygalic acid B, pachymaran 50 Part.
Prepare embodiment 14 --- the preparation of pharmaceutical composition
For treating the pharmaceutical composition of senile dementia disease, it is made of the raw material of following parts by weight:Alpha-ararin 3 Part (being purchased from Jinan Hai Liheng Pharmaceutical Technology Co., Ltd), 10 parts of tenuifolin, 3 parts of polygalic acid B, Radix Polygalae polysaccharide 40 Part, 20 parts of grass-leaved sweetflag polysaccharide.
Pharmacological Examples 1 --- the present composition acts on the memory improvement of reproducibility dysmnesia mouse caused by ethyl alcohol
Laboratory apparatus
Title:8 mouse keep away scotopia screen analysis system
Model:JLBehv-STG-8
Source:Jiliang Software Sci-Tech Co., Ltd., Shanghai
Experimental animal
Strain:ICR mouse
Gender:Male
Weight:16-18g
Source:Western Poole-Bi Kai experimental animals the Co., Ltd in Shanghai
1 mice group of table and administration
Experimental method:
Each group mouse press 1 oral gastric infusion (i.g.) of table, 1 times/day, 0.2ml/10g weight, successive administration 3 weeks.Last 1h after administration, with darkness avoidance test training once.Mouse is put into and is kept away in camera bellows, bright room is put into facing away from hole, while starts screen point Analysis apparatus, animal enter darkroom through hole and are shocked by electricity, and timing is automatically stopped.Mouse is taken out, screen analysis will the every mouse of record From bright room is put into the time run into darkroom needed for electric shock, this i.e. incubation period.It is tested afterwards for 24 hours, 30min is passed through before test Mouth gavage gives 45% ethanol solution (0.1ml/10g), and screen analysis system will produce and record all correlations of animal automatically Data.
Data Processing in Experiment:
Data are with mean+SDIt represents, data difference statistics is using one-way analysis of variance (ANOVA), group difference is with P<0.05 judges.
The effect of reproducibility dysmnesia caused by verifying pharmaceutical composition Anti-ethanol of the present invention by zoopery, the result is shown in Table 2.
2 gastric infusion of table influences reproducibility dysmnesia mouse caused by ethyl alcohol by test product
" * " represents P < 0.05;" * * " represents P < 0.01vs model groups
As seen from the experiment, gavage is given and prepares embodiment 1, prepares embodiment 2 and prepare embodiment 10 after by test product The bright room of reproducibility dysmnesia mouse caused by ethyl alcohol can be significantly increased enters the incubation period in darkroom, but prepare embodiment 10 effectively into The drug effect statistics of subassembly object is better than not purified crude extract (preparation Examples 1 and 2).
Therapeutic effect of Pharmacological Examples 2 --- the present composition to transgenosis AD mouse
Above-described embodiment shows that Poria cocos, grass-leaved sweetflag and Radix Polygalae crude extract have certain anti-AD activity, but after purification effective Component composition drug effect statistics is better than crude extract.To verify the drug action of active ingredient composition, this EXPERIMENTAL EXAMPLE It is tested using more advanced transgenosis AD mouse models.
Experiment selects trangenic mice source as the jackson laboratory, number 004462, http:// jaxmice.jax.org/strain/004462.html.By APPswePS1deltaE9 double transgenics male AD mouse and female B6C3F1 mouse mate, and it is small to distinguish APPswePS1 deltaE9 double transgenics AD that pcr gene identification is carried out to its generation mice Mouse and negative non-transgenic control mouse.
Key instrument:Morris water mazes be diameter 1.2m, high 40cm drums, depth of water 25-30cm, divide four quadrants. Escape platform diameter 10cm, it is seen that platform is placed in 0.5cm on the water surface, and invisible platform is placed in underwater 1cm.By automatic orbit with Track system record mouse swimming track.
Animal packet and medication (being shown in Table 3):It is more than the APPswePS1deltaE9 double transgenics of 16 weeks using mouse age Mouse and negative non-transgenic control mouse, AD mouse are randomly divided into investigational agent group and saline control group, and negative transgenosis is small Mouse gives physiological saline, and daily gastric infusion once, after medication 2 months, carries out determined with Morris water.
3 mice group of table and administration
The behavioral indexes detection of learning and memory of little mouse:Water maze laboratory is the master for testing mouse Spatial memory ability Want one of experimental method.Experiment can escape the instinct in waters based on mouse as far as possible, and training mouse passes through the space beyond water tank The ability in mark identification orientation.It is showed by testing each group mouse behaviouristics in Morris water mazes, compares AD before and after medication Whether the learning memory disorder of mouse makes moderate progress.Specific method is as follows:(1) the 1st to the 2nd day:Visible platform is placed in quadrant The heart, mouse head are gently put into pond towards pool wall, and record mouse from water is entered, to the time climbed up needed for platform, (escape by visible platform Incubation period).Training 8 times daily of every mouse, every time training are put into position and randomly choose one of four quadrant separator bars, platform with Machine is placed on the center of one of four quadrants.(2) the 3rd to the 8th days:Invisible platform fixation is placed on the center of a certain quadrant, does not make Change.Record mouse is from water is entered to the time climbed up needed for platform (invisible platform is escaped incubation period).Every mouse is instructed daily Practice 4 times, training every time is put into position and randomly chooses one of four quadrant separator bars, every time training interval 20-40 minutes.(3) the 9th My god:Not placement platform.Mouse is allowed to freely explore 1 minute after entering water, records the movement locus of mouse therebetween, statistics mouse is in original Quadrant search time percentage where platform.
Data Processing in Experiment:Experimental result is represented with mean value ± standard error (x ± SD).It is united using ANOVA analyses Meter analysis, judges whether with significant.
Experimental result:Mouse morris water maze laboratories the results show that compared with negative transgenosis group, AD- control groups Invisible platform escape incubation period is obviously prolonged, and ANOVA analysis differences have conspicuousness, it was demonstrated that AD transgene mouse models exist Learning memory disorder.
Compared with AD- control groups, the escape incubation period of the invisible platform of AD- investigational agent groups is obviously shortened, and ANOVA analyses are poor It is different that there is conspicuousness (being shown in Table 4 and Fig. 1), by reagent is prompted to can obviously improve the learning memory disorder of AD mouse.
Invisible platform escape incubation period (second) of 4 mouse of table
4 note of table:The invisible platform escape latency (second) of mouse morris water mazes:Mean value ± standard error.It is negative Transgenosis group vs AD- control groups, two way ANOVA analysis P=0.031;AD- control group vs AD- reagent groups, two factors ANOVA analyzes P=0.05.
5 mouse target quadrant search time percentage (%) of table
5 note of table:Mouse is freely explored 1 minute in the water maze for not being placed with platform, statistics mouse where original platform as Limit search time percentage, mean value ± standard error.Negative transgenosis group vs AD- control groups, t examine P=0.005;AD- is compareed Group vs AD- investigational agent groups, t examine P=0.038.
Mouse morris water maze laboratory the results shows:Compared with negative transgenosis group, AD- control groups where platform as Limit search time is remarkably decreased, and ANOVA analysis differences have conspicuousness, it was demonstrated that there are learning and memory barriers for AD transgene mouse models Hinder.Compared with AD- control groups, investigational agent group quadrant search time where platform is higher than saline control group (see Fig. 2), poor It is different that there is conspicuousness, investigational agent is prompted to can obviously improve the learning memory disorder of AD mouse.
We further detect mouse visible platform escape incubation period (being shown in Table 4 and Fig. 1) and swimming rate (table 6 and Fig. 3), No significant difference between the results show each group eliminates the invisible platform caused by dysopia or locomitivity are damaged and escapes Raw preclinical difference.The AD mouse memories damaging action the experimental results showed that investigational agent has clear improvement above.
Further study show that compared with AD- control groups, AD- test groups do not influence mouse swimming rate (table 6, Fig. 3), The learning memory disorder effect that prompting investigational agent improves AD mouse is realized not by mouse swimming rate is influenced.
6 mouse swimming rate (cm/s) of table
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited It encloses.

Claims (10)

  1. It is 1. a kind of for treating the pharmaceutical composition of senile dementia disease, which is characterized in that the pharmaceutical composition include with Lower active ingredient and pharmaceutically acceptable excipient, carrier, adjuvant or its combination;
    Wherein, the active ingredient is selected from the group:Pachymic acid, alpha-ararin, β-asarone, tenuifolin, Radix Polygalae soap Glycosides B, Radix Polygalae mouth mountain ketone III, pachymaran, grass-leaved sweetflag polysaccharide, Radix Polygalae polysaccharide or its combination.
  2. 2. pharmaceutical composition as described in claim 1, which is characterized in that contain 3~9 kinds of the active ingredient.
  3. 3. pharmaceutical composition as described in claim 1, which is characterized in that contain 6~9 kinds of the active ingredient.
  4. 4. pharmaceutical composition as described in claim 1, which is characterized in that contain 8~9 kinds of the active ingredient.
  5. 5. pharmaceutical composition as described in claim 1, which is characterized in that in the pharmaceutical composition:
    The content of pachymic acid be more than 0.05wt% and/or
    The content of alpha-ararin be more than 0.01wt% and/or
    The content of β-asarone be more than 0.1wt% and/or
    The content of tenuifolin be more than 0.3wt% and/or
    The content of polygalic acid B be more than 0.2wt% and/or
    The content of Radix Polygalae mouth mountain ketone III be more than 0.05wt% and/or
    The content of pachymaran be more than 1.0wt% and/or
    The content of grass-leaved sweetflag polysaccharide be more than 1.0wt% and/or
    The content of Radix Polygalae polysaccharide is more than 1.0wt%,
    And pharmaceutically acceptable excipient, carrier, adjuvant or its combination of surplus;More than content presses the medicine group Close the gross weight meter of object.
  6. 6. pharmaceutical composition as described in claim 1, which is characterized in that the pharmaceutical composition, which further includes, to be selected from the group Auxiliary element:Poria cocos eo-acid A, Poria cocos eo-acid B, Roots of Polygala tenuifolia glycosides A, 3,6 '-two mustard acyl sucrose or its combination.
  7. It is 7. a kind of for treating the pharmaceutical composition of senile dementia disease, which is characterized in that the pharmaceutical composition it is effective Ingredient includes the active ingredient in fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia;
    And the active ingredient in the fushen or Poria cocos, grass-leaved sweetflag and Polygala tenuifolia includes:Pachymic acid, alpha-ararin, β-thin Pungent brain, tenuifolin, polygalic acid B, Radix Polygalae mouth mountain ketone III, pachymaran, grass-leaved sweetflag polysaccharide and Radix Polygalae polysaccharide.
  8. 8. pharmaceutical composition as described in claim 7, which is characterized in that contain effective active in the pharmaceutical composition Ingredient is as follows:
    The pachymic acid of 2-10 parts by weight;
    The alpha-ararin of 1-10 parts by weight;
    β-asarone of 1-20 parts by weight;
    The tenuifolin of 5-50 parts by weight;
    The polygalic acid B of 3-30 parts by weight;
    The Radix Polygalae mouth mountain ketone III of 1-10 parts by weight;
    The pachymaran of 20-200 parts by weight;
    The grass-leaved sweetflag polysaccharide of 20-200 parts by weight;
    The Radix Polygalae polysaccharide of 20-200 parts by weight;
    And the total weight of the effective active composition accounts for the 20-99% of pharmaceutical composition total weight and pharmaceutically may be used for surplus Excipient, carrier, adjuvant or its combination of receiving.
  9. 9. pharmaceutical composition as described in claim 7, which is characterized in that contain effective active in the pharmaceutical composition Ingredient is as follows:
    The pachymic acid of 3-4 parts by weight;
    The alpha-ararin of 3-4 parts by weight;
    β-asarone of 4-6 parts by weight;
    The tenuifolin of 8-10 parts by weight;
    The polygalic acid B of 4-8 parts by weight;
    The Radix Polygalae mouth mountain ketone III of 3-6 parts by weight;
    The pachymaran of 30-100 parts by weight;
    The grass-leaved sweetflag polysaccharide of 20-100 parts by weight;
    The Radix Polygalae polysaccharide of 30-100 parts by weight;
    And the total weight of the effective active composition accounts for the 50-99% of pharmaceutical composition total weight.
  10. 10. a kind of purposes of pharmaceutical composition as claimed in any one of claims 1 to 9 wherein, which is characterized in that be used to prepare and control Treat the drug of senile dementia.
CN201611038340.9A 2016-11-23 2016-11-23 A kind of pharmaceutical composition for being used to treat senile dementia disease Pending CN108079009A (en)

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